We propose to use behavior genetic methods to investigate olfaction in humans and animal model. These methods have been used successfully in studies of other sensory systems (vision, audition) but have not been systematically employed in studies on the chemical senses. In human studies, we will investigate the relationship between olfactory sensitivity to substances for which selective hyposmias (or odor "blind spots") have been reported and genes located within or linked to the major histocompatibility complex. This complex (HLA) contains genes responsible for tissue graft rejection and other immune responses. The hypothesis which we will test, proposed initially by Lewis Thomas, is that the similarities between the immune system and olfaction (e.g., specific recognition abilities of both systems for a large number of chemicals) are due to the two systems sharing a common genetic basis. The human subjects will be families obtained by the investigators at Memorial Sloan-Kettering Cancer Center (SK). These families will have been typed for HLA and other genetic markers. Subsequently, tests of olfactory sensitivity to selected odors will be conducted and appropriate statistical analyses will be conducted to determine genetic pleiotropy or linkage. Our work with mice will be two-pronged. Animal models will be developed from genetically inbred, congenic and recombinant lines of mice either commercially available from The Jackson Laboratory, supplied from Section 6126 of SK, or produced in our colony. We have already described one possible mimic of a human phenotype - insensitivity to isovaleric acid. We will investigate the genetic preconditions and functional deficits in the TH's model through behavioral genetic and neuroanatomical methods. Additionally, we will seek other models of human phenotypes among domestic mice for future anatomical, electrophysiological and biochemical studies. The strong association between some diseases and HLA antigens offers outstanding genetic markers for these diseases. Tests of olfactory sensitivity may parallel HLA typing in the diagnosis, prognosis, treatment and prevention of some diseases.